An assessment of the potential developmental and reproductive toxicity of di-isoheptyl phthalate in rodents.

Di-isoheptyl phthalate (DIHP) is a branched, phthalate ester with seven carbon alkyl side chains. Since structurally similar phthalates have been shown to produce developmental and/or reproductive effects in rodents, the potential for DIHP to produce developmental and reproductive toxicity was assessed. In a developmental toxicity study, female rats were given DIHP by oral gavage on gestational days 6-20. There were significant reductions in uterine weight, increased resorptions and reduced fetal weight in the high dose (750 mg/kg) group. Fetal examination revealed malformations and variations of both the skeletal system and the viscera including ectopic testes. The intermediate dose, 300 mg/(kg/day), was a no effect level in this study. In a two-generation reproductive toxicity study, DIHP was given in the diet at 1000, 4500 and 8000 ppm. In the 8000 ppm group of the first (F1) generation, anogenital distance was reduced, time to balanopreputial separation was increased, there was a significant increase in thoracic nipples and testicular abnormalities, and weights of testes and accessory reproductive organs were significantly reduced. Testicular sperm counts and daily sperm production were significantly reduced. Fertility was also significantly reduced in the 8000 ppm group. In the second (F2) generation offspring, anogenital distance was significantly reduced and there was evidence of reduced weight gain during lactation in both the 4500 and 8000 ppm groups. The overall no effect level (NOEL) in the reproductive toxicity study was in the range of 64-168 mg/(kg/day) (gestation-lactation periods). By comparison, estimated average human exposures in the general population are <1 microg/(kg/day).